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Cancer Discov. 2019 Sep;9(9):1268-1287. doi: 10.1158/2159-8290.CD-18-1409. Epub 2019 Jul 1.

Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.

Author information

1
Cancer Research UK Beatson Institute, Glasgow, United Kingdom.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
3
Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
4
Medical Scientist Training Program, Stony Brook University, Stony Brook, New York.
5
Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
6
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
7
Cambridge Advanced Imaging Centre, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
8
The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
9
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
10
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom.
11
The Francis Crick Institute, London, United Kingdom.
12
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. Dtuveson@cshl.edu.
#
Contributed equally

Abstract

Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.This article is highlighted in the In This Issue feature, p. 1143.

PMID:
31263025
PMCID:
PMC6726540
[Available on 2020-03-01]
DOI:
10.1158/2159-8290.CD-18-1409

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